Regulatory aspects of Phyto-Pharmaceuticals

Transcription

1 Regulatory aspects of Phyto-Pharmaceuticals Fellow of the Royal Society of Chemistry [FRSC], U.K Common Wealth Fellowship, UK BOYSCAST Fellowship, DST Biotechnology Overseas Award, DBT AICTE Career Award For Young Teachers DIA Out Standing Service Award, USA DST-JSPS Visiting Fellow Japan The Fujii Otsuka Award Japan DIA Research Grant Award, USA APTI Young Pharmacy Teacher Award, IPA Fellowship Award Visiting Scientist at the : King s College London Tokushima University Leiden University, The Netherlands School of Pharmacy, London Medical Research Council, Cape Town Pulok K. Mukherjee, PhD, FRSC Director School of Natural Product Studies Jadavpur University Kolkata ; India naturalproductm@gmail.com Associate Editor, J. Ethnopharmacology, Elsevier Science Emerging Needs and Regulations on Phytopharmaceuticals India International Centre, New Delhi June18, 2014

2 Phytomedicines in Different Countries Variable Situations Strong foundation of traditional medicines having nationally recognized parallel traditional systems along with western medicine India and China Europe and USA A new and growing consumer interest in natural medicine but not recognized by the governments including drug authorities Move to give legitimacy to the traditional healers even after western medicine made its appearance and took firm roots Africa

3 Regulation and promotion of botanicals varies which has a global impact throughout International co-ordination is the need of the day for proper regulation and promotion of botanicals in alternative medicine Highlights of the discussion Development of alternative medicine Role of botanicals [herbals] in these systems Understanding the current regulations on phyto medicines and international co-ordination on its different aspects

4 Indian System of Medicine (ISM) Traditional health care system of India It covers all the systems which originated in India and out side got adopted and adapted in course of time: but Unani ( BC) Siddha ( BC) Ayurveda ( BC) ISM Homeopath y (1850 AD) Yoga and Naturopathy Mukherjee & Wahile, 2006, J. Ethnopharmacology 103, Botanicals constitute a major part in ISM Indian Materia Medica includes about 2000 drugs of natural origin 1250 Indian medicinal plants are used in therapeutic formulations in ISM About 85% of ISM preparations are poly - herbal - Therapeutic Validation of herbal medicine - Phytochemical validation - Metabolomic studies, chemo profiling, quality control and standardization

5 Food as Medicine: A Systemic Approach for Validation of Therapeutic efficacy Mukherjee et al., Food Chem Toxicol, 49,

6 Screening of drugs as AChE inhibitors (drug development for Alzheimer s disease) Acorus calamus Linn. (Acoraceae) β-asarone Clitoria ternatea (Fabaceae) Taraxerol Phytomedicine, Elsevier, 2010, 17: Trigonella foenum graecum (Fabaceae) Trigonelline Murraya koenigii (Rutaceae) Mahanibine Phytother. Res. Wiley, 2010, 17: CH 3 OH HO O OH Illicium Verum (Illiciaceae) H 3 CO Anethole Marsilea quadrifolia (Marsileaceae) HO O OH Quercetin Fitoterapia, Elsevier, 2011, 82: Piper betel (Piperaceae) Chlorogenic acid Hydroxychavicol Mini Review in Medicinal Chemistry, Bentham, 2011, 11: Natural Product Research, 2012, 26: Orient Pharm Exp Med, 2013, DOI /s

7 India drug gives Alzheimer's hope Scientists in the UK and India are examining the ancient Indian ayurvedic medicine for possible use in drugs to treat Alzheimer's disease. India drug gives Alzheimer's hope Researchers say ayurveda works in the same way as conventional drugs for boosting mental agility in the disease. They found that the plants used in ayurveda acted to improve memory and concentration in Alzheimer's sufferers. Alzheimer's disease is a progressive, degenerative and irreversible brain disorder. There is no known cure. The disease causes intellectual impairment, disorientation and eventually death. Researchers from King's College, London and Jadavpur University in the eastern Indian city of Calcutta, studied five plants commonly used in ayurvedic medicine. They found that the plants acted to prevent the breakdown of neurotransmitters, improving memory and concentration in people with Alzheimer's disease - the most common form of dementia. The scientists are now trying to identify the chemical compounds responsible so they can be used to develop more effective drugs. There is no known cure for Alzheimer's disease

8 HERBAL DRUGS NOT AS SAFE AS THEY ARE PROMOTED Assuming that everything that is NATURAL is SAFE is not correct! Herbal drugs are not uniformly regulated, many claims can be made that are poorly documented! Other contaminants Authentication & Reproducibility of herbal ingredients Adulteration /Substitution Toxic metals Problems with regulated herbal products Microbial contamination Fumigants Pesticides Mukherjee et al., 2011, Botanicals as medicinal food and their effects on drug metabolizing enzymes. Food Chem Toxicol.,, 49,

9 Chemo-profiling Quality control and standardization Marker analysis Bioactive compound Quantification Mukherjee et al, 2011, Drug Information Journal, Vol. 45, pp Spurious drug determination Comparative fingerprint analysis Pandit et al., Biomed.chromatogr., 25: Standardization of herbs Gantait et al; 2010, JOURNAL OF AOAC INTERNATIONAL: 93 Stability of formulations Mukherjee et al; 2010, Phytochem. Anal, 21, Mukherjee et al; 2009, Phytochem. Anal. 19: Quality consistency

10 Quality related safety issues Safety evaluation of medicinal plants CYP 450 enzyme inhibition Quantitative estimation Supersomes assay CYP P450 - CO complex method Fluorometric microtiter plate assay HPLC assay Estimated based on metabolites formation Mukherjee et al., Food Chem Toxicol, 49, Quantitative Estimation of CYP by Microplate Reader CYP P450 + CO CYP P450--CO Yellow complex 450 nm Pandit et al., Food Res. Int.. Res. 45: Enzyme : CYP3A4/CYP2D6 Substrate :BFC (7-Benzyloxy- trifluromethylcoumarin) Positive control : KTZ (Ketoconazole) Cofactors:1.3 mm NADP+, 66 mm MgCl 2 & 66 mm Glucose 6-Phosphate Glucose 6-Phosphate Dehydrogenase:40Unit/mL in 5 mm Sodium Citrate Buffer (ph 7.5) Stop reagent : 0.5 M Tris Base Test extract : Plant extract (0.5 mg/ml) provided by CCRAS Metabolite standard: HFC (7-Hydroxy- trifluorocoumarin) Pandit et al., Phytother. Res. 25: Ponnusankar et al. 2011, Phytother. Res.,133: Pandit et al., Fitoterpia., 82:

11 Validation of traditional Formulations Evidence based approach Triphala Tri Three Phala- Fruits Ellagic acid Ponnusankar et al., J. Ethnopharmacology 133,

12 Global issues for promotion of natural products Quality control Safety of the herbal preparations Development of effective marker Clinical efficacy of marker Documentation Regulatory harmonization

13 Pharmacopoeial Laboratory for Indian Medicine (PLIM) Homoeopathic Pharmacopoeial Laboratory (HPL) Ayurved Hospital, Lodhi Road, New Delhi Central Council for Research in Ayurveda and Siddha (CCRAS) Central Council for Research in Unani Medicines (CCRUM) Central Council for Research in Homoeopathy (CCRH) Central Council for Research in Yoga & Naturopathy (CCRYN) National Medicinal Plant Board Four Research councils Board Three subordinate offices AYUSH One public sector undertaking Eight educational institutions Two statutory organizations Indian Medicine Pharmaceutical Corporation (IMPCL) The Central Council of Indian Medicine (CCIM) The Central Council for Homoeopathy (CCH) National Institute of Ayurveda (NIA), Jaipur National Institute of Siddha (NIS), Chennai National Institute of ayurveda research, Kolkata National Institute of Naturopathy (NIN), Pune National Institute of Unani Medicine, Bangalore Institute of Post Graduate Teaching & Research in Ayurveda, Jamnagar (Gujarat) Rashtriya Ayurveda Vidyapeeth, New Delhi Morarji Desai National Institute of Yoga, New Delhi

14 Acts Administered in the ISM Sector Central Council of Indian Medicine Act 1973 Central Council of Homoeopathy Act 1973 Drugs & Cosmetics Act and Rules there under. Drugs & Magic Remedies [Objectionable Advertisement] Act -1954, 1955 and Rules there under. Medicinal and Toiletries Preparation acts and Rules

15 Regulation of ASU Drugs Regulation of herbal medicines deals with regulatory status of herbal medicines, regulation requirements, products and quality control requirements such as GMP, monographs, etc.

16 Provisions Relating To ASU Drugs: D&C Act Sections Subject 33C. Ayurvedic, Siddha and Unani Drugs Technical Advisory Board. 33D. The Ayurvedic, Siddha and Unani Drugs Consultative Committee. 33E. Misbranded drugs 33EE. Adulterated drugs. 33EEA. Spurious drugs. 33EEB. Regulation of manufacture for sale of ASU drugs 33EEC. Prohibition of manufacture and sale of certain ASU drugs. 33EED. Power of Central Government to prohibit manufacture, etc., of ASU drugs. in public interest. 33F. Duties of Government Analysts. 33G. Powers of Inspectors. 33H. Application of provisions of sections 22, 23, 24 and EEB. Regulation of manufacture for sale of ASU drugs. 33EEC. Prohibition of manufacture and sale of certain ASU drugs. 33EED. Power of Central Government to prohibit manufacture, etc., of ASU drugs. 33F. Government Analysts. 33-I. Penalty for manufacture, sale, etc., of ASU drugs. 33J. Penalty for subsequent offences. 33K. Confiscation. 33L. Application of provisions to Government departments. 33M. Cognizance of offences. 33N. Power of Central Government to make rules. 33O. Power to amend First Schedule

17 The regulations on ISM drugs in India mainly deals with.. To lay down standards of single drug or compound formulations included in ASU To establish a drug depot of genuine crude drug samples after collecting them from different agro climatic zone of the country To ensure an appropriate infrastructure or quality system encompassing the organizational structure, procedures, process and resources. To ensure adequate confidence that the botanicals satisfy the prescribed requirement for quality. Procurement and documentation of Traditional methods of quality control. Interpretation of the traditional information about identification and quality assessment in terms of modern technology. Development of concrete methods of identification and quality assurance in terms of modern methodologies.

18 Introduction of Rule 160 A-J dtd for approval of laboratories from private sector for testing of ASU drugs and raw materials ( )

19 Rules & Regulation of ISM The Good Manufacturing Practices for ASU Drugs as described in Rule 157 of Drugs & Cosmetics Rules 1945 with conditions as specified in Schedule T / GMP are to ensure that: (I) Raw materials used in the manufacture of drugs are authentic, of prescribed quality and are free from contamination (II) The manufacturing process is as has been prescribed to maintain the standards (III) Adequate quality control measures are adopted (IV) The manufactured drug which is released for sale is of acceptable quality (V) To achieve the objectives listed above, each licensee shall evolve methodology and procedures for following the prescribed process of manufacture of drugs which should be documented as a manual and kept for reference and inspection. However, under IMCC Act, 1970 registered Vaidyas, Siddhas and Hakeems who prepare medicines: on their own to dispense to their patients and not selling such drugs in the market are exempted from the purview of Good manufacturing Practice (GMP)

20 Regulation on Safety study incorporated Rule 168 B dt

21 Official Compendium Ayurvedic pharmacopoeia of India Part I: Volume Year of publishing No of monographs I II III IV V VI VII (Minerals And Metals) Ayurvedic pharmacopoeia of India Part II: Volume Year of publishing No of monographs I II III Ayurvedic formulary of India: Part Year of publishing No of monographs I II

22 WHO guidelines for herbal medicinal products

23 National Policy on Traditional Medicine and Regulation of Herbal Medicine Assessment of safety and efficacy 28 monographs in monographs in monographs in monographs In 2009 WHO Monographs on Selected Medicinal Plants - Volume 1-4

24 National Policy on ISM Strategies: Objective: Policy support, Financing ISM & H and Medical Education Drug Standards, Regulation & Enforcement To promote good health and expand the outreach of health care through ISM Medicinal Plants and The ISM Industry Intellectual Property Rights (IPR) of ISM To improve the quality of teachers, clinicians and researchers Revitalization of Local Health Traditions Medical Tourism and Export of ISM Practitioners Ancient Medical Manuscripts and Research in ISM To improve the infrastructural facilities To ensure safe and efficacious use of drugs in ISM Access to information and Veterinary Medicine To facilitate pharmacopoeial standards of raw material Integration of ISM & H and National Health Care Programmes and Delivery System, Drug Standardization and Quality Control Exposing the Foreign and Indian Modern Graduates to Indian Systems of Medicine (ISM) and Building Awareness Integrate ISM in health care delivery system and clinical practice To aware public globally for use of herbal products To provide full opportunity for the growth and development of ISM ( )

25 Grey areas Promotion and development of herbs 356 monographs are included in 4 volumes of Ayurvedic Pharmacopoeia of India, so what are the standards of remaining about 1644 herbs used in Ayurvedic system of medicines? What are the standards of numerous Ayurvedic multiingredient formulations? Chemical characterization is not stringent enough in Ayurvedic Pharmacopoeia. Involvement of Modern Instrumentation techniques are required. More in-depth validation is required

26 Developments Framing of Legislation on Nutritional Supplement. Amendment of Schedule T (GMP for Ayurvedic Drug Manufacturing Units)and its implementation. Inclusion of 88 Monographs of Herbal Drugs in the latest edition of Indian Pharmacopoeia Permitted Excipients ( ): As mentioned in the Indian Pharmacopoeia, Prevention of Food Adulteration Act, Proposal for displaying of the ingredients on Labels of Ayurveda, Siddha & Unani Drugs. Heavy metal testing made mandatory (2006): Arsenic, Lead, Mercury and Cadmium (not more than 20 ppm) Maintaining of records of raw materials used by licensed manufacturing units of Ayurveda, Siddha and Unani (ASU) drugs(rule-157a, dt ) Stipulation of Expiry date for Ayurvedic Medicines (Rule-162 B dtd ) Regulation on Safety study incorporated (Rule 168 B dt )

27 Challenges - Globalisation From world wide application of traditional medicines and different regulatory systems towards global harmonised standards

28 A Systematic Approach for Validation of Traditional medicine Mukherjee et al., J. Ethnopharmacology,143 :

29 International coordination Strategies to mainstream the indigenous system of medicine To promote medical pluralism Medical Pluralisms: - Building bridges to increase communication & to support ethical collaborations & co-operations on use of natural products with out interfering with their individual autonomy

30 Globalization of Traditional Medicine 12 th International Congress of Ethno-pharmacology February ISE 2012, 17-19, 2012; Kolkata, India Inaugurated by Honourable Dr. A. P. J. Abdul Kalam, former President of India Keynote speaker was Prof. Luc Montagnier, Nobel laureate in Medicine Over 1000 delegates from 52 countries Over 600 scientific presentations

31 SOCIETY FOR ETHNOPHARMACOLOGY 23/3, Saktigarh, Jadavpur, Kolkata: , India Registered under the West Bengal Society Registration Act 1961 Mission: Promotion of Ethnopharmacology and validation of medicinal plants and other natural products Globalizing local knowledge and localizing global technologies Society For Ethnopharmacology India Welcome You for India Chapter Mission and Providing an environment for knowledge sharing among researchers, healthcarepractitioners, and decision-makers interested in Ethnopharmacology Globalization of local knowledge and localizing global technologies Organizing conference, seminars, symposiums, workshops etc in different parts of India for dissemination of knowledge Inculcating scientific temperaments for validation of medicinal plants and natural products Encouraging the scientists through awards, honors etc.

32 Globalizing Traditional Medicine: Present and Future prospects Inaugurated by His Excellency Sri Shekhar Dutt, Governor of Chhattisgarh Keynote speaker was also Sri Shekhar Dutt, Governor of Chhattisgarh Over 700 delegates from 20 countries Over 300 scientific presentations

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34 Herbal Pharmacovigilance Dissemination of knowledge for promotion of natural products Quality control & standardization Phytochemical & pharmacological screening Chemo-profiling of natural products Globalization of traditional medicine School of Natural Product Studies Jadavpur University, Kolkata Scientific validation of medicinal plants Formulation & evaluation of herbal medicine Lead finding from natural products High-throughput screening methodology for medicinal plant Herbal therapeutics & pharmacokinetics Safety evaluation of herbal drugs Evidence based approaches for development of tradition medicines Development & evaluation of nutraceuticals and dietary supplements Bioassay guided isolation & lead finding in natural products

35 Books & Proceedings published from SNPS, JU, India

36 Involvement with Peer-reviewed Publications worldwide Editor and Editorial Board member

37 Acknowledgement Faculdade de Farmácia da UFMG Brazil CSIR Pulok K. Mukherjee, PhD, FRSC CCRAS Associate Editor, J. Ethnopharmacology, Elsevier Science Healing plants are Nature s Gift for Everyone